Niclosamide Encapsulated pH‐Responsive Polyzwitterionic Block Copolymers for Cancer Therapy

Niclosamide (NIC) shows antitumor activity by inhibiting multiple signaling pathways, including signal transducer and activator of transcription 3, Wnt/β-catenin, and NF-κB. However, the poor aqueous solubility and bioavailability limit its potential in treating systemic diseases. To address this, we report here the synthesis of a pH-responsive block copolymer PLLA-b-PDMAEMA-Q based on poly(L-lactide) (PLLA) and poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) diblock copolymer. First, the PLLA block was prepared by ring-opening polymerization (ROP) followed by the diblock, by atom transfer radical polymerization (ATRP) to prepare PLLA-b-PDMAEMA. Three different block copolymer compositions were synthesized by varying the molecular weight ratio of PLLA to PDMAEMA at 1:2, 1:1, and 1:0.5. PLLA-b-PDMAEMA was then quaternized by reaction with bromoacetic acid to generate PLLA-b-PDMAEMA-Q. In aqueous solution, these copolymers were found to self-assemble into micelles with a hydrodynamic diameter of 79-107 nm. PLLA-b-PDMAEMA-Q was converted to its polyzwitterionic analogue PLLA-b-PDMAEMA-ZIP in PBS buffer (pH 7.4) and used for encapsulation of NIC. The NIC-loaded PLLA-b-PDMAEMA-ZIP (ZIP-NIC) showed a spherical morphology with a hydrodynamic diameter of 230 ± 15.81 nm and significant uptake in HCT116 cells. ZIP-NIC exhibited similar anti-cancer efficacy to free NIC in the HCT116 cell line. Our results suggest that polyzwitterionic nanoparticles constitute a promising class of materials to deliver antitumor drugs and warrant further investigation.